This project focuses on basic and applied research on human retroviruses, HIV-1 and HTLV-I. It covers three broad areas--I) basic research studying the regulated expression of HIV-1; II) basic research on cellular transformation events as related to HTLV-I; and III) applied research towards developing HIV-1-based vectors and designing molecular ribozymes targeted against HIV-1. Some notable scientific findings from our research program in 1996-1997 include: 1) the demonstration that the promoter activity of Tat functions at a step subsequent to TBP-recruitment; 2) evidence that intravirion delivery of Tat indicates a role for this protein at a pre-integration step; 3) the finding that HIV-1 Tat modulates DNA-PK-mediated phosphorylation of Sp1; 4) the identification of a novel human thioredoxin peroxidase that regulates IkappaB-alpha phosphorylation and NF-kappaB activation; 5) the elucidation of HTLV-I Tax dimerization as being required for optimal trans-activation; 6) the observation of an interaction between HTLV-I Tax and cytokeratin that results in changes in keratin-containing cytoskeletal networks; 7) the clarification of an effect of Tax on cell cycle progression that impinges on the cellular roles of cyclin D-cdk and p110RB; 8) the isolation of a human suppressor of JNK1 activation by TNFa; 9) the generation of infectious HIV viral particles containing a therapeutic ribozyme; and 10) the efficient expression using an alphavirus replicon of a functional ribozyme targeted to HIV-1. In the coming year, we plan to continue research extensions into each of the three areas of focus.